1. Field of the Invention
The present invention relates generally to the fields of molecular endocrinology and peptide chemistry. More specifically, the present invention relates to a novel method of treating tumors using GnRH-III.
2. Description of the Related Art
Gonadotropin-Releasing Hormone (GnRH; also known as Luteinizing Hormone Releasing Hormone or LHRH) is a major hypothalamic peptide hormone responsible for stimulating the release of Luteinizing Hormone and Follicle Stimulating Hormone from the anterior pituitary. The primary structure of GnRH has been determined in, inter alia, mammals, salmon, catfish, chicken, and most recently, lamprey.
Lamprey GnRH differs in five amino acids compared with salmon GnRH, dogfish GnRH and chicken GnRH-II. A second form of GnRH exists in lamprey and this form (GnRH-II) differed from lamprey GnRH-I by three residues (Ile, Phe and His instead of Glu, Lys, and Tyr). More recently, a third immunoreactive form of lamprey GnRH has been discovered, lamprey GnRH-III.
Analogs of GnRH are known to inhibit the growth of mammary tumors and do so by two mechanisms: (1) estrogen deprivation; and (2) a direct effect on cancer cells. It is well known that gonadectomy is a necessary therapeutic intervention in the management of gonadal steroid dependent tumors. The GnRH analogs can exert their antitumor activity not only through chemical castration but also by directly affecting the tumor cells. The presence of GnRH binding sites in human mammary cancer cells has been previously reported. Mammary tumor cell membranes contain both high and low affinity binding sites. Moreover, human breast cancer cell lines, such as MDA-MB-231 and ZR-75-1, express the GnRH gene. GnRH analogs interact directly with mammary tumor and activate a G-protein dependent transducing mechanism. Previous studies indicated that the direct growth inhibition of mammary tumor cell lines is achieved with relatively high analog concentrations, e.g., 10.sup.-6 to 10.sup.-5 M. The peptide levels correspond with apparent binding to low affinity receptors on the mammary cancer cells. According to the prior art, a GnRH antagonist (SB-75) interferes most likely with the autocrine loop of IGF-II and several levels, namely, IGF-II secretion, production of IGF-I binding proteins and the effect of IGF-II on cell growth.
The amino acid sequence of GnRH-III is known and was isolated from the sea lamprey, Petromyzon marinus. GnRH-III has 60% homology to mammalian GnRH. GnRH-III is the first peptide in the GnRH family which has an Asp residue at position six.
The prior art is deficient in the lack of effective means of inhibiting the growth and proliferation of mammary tumor cells and in treating breast cancer generally. The present invention fulfills this longstanding need and desire in the art.